REVIEW:- INDUSTRIAL PROCESS VALIDATION OF TABLET DOSAGE FORM
1Abhijeet Welankiwar*, Sushant tope.
1Government College of pharmacy
kathora naka Amravati (Maharashtra) 444604.
The validation is a Fundamental segment that supports to a commitment of company towards quality assurance. It also assures that product meets its predetermined quality specification and quality characteristics. Validation of individual step of manufacturing is called as process validation. Here this article concerns with the process validation of tablet dosage form which has a numerous advantages over other dosage forms. The objective is to present a review and to discuss aspects of validation in terms of pharmaceutical unit operations; that is, those individual technical operations that comprise the various steps involved in product design and evaluation.
REFERENCE ID: PHARMATUTOR-ART-1760
As per USFDA Process validation is “establishing documented evidence which provides high degree of assurance that a specific process will consistently produce a product meeting its predetermined Quality specifications and Quality characteristics”. The process validation is of 4 Types: -
1) Prospective validation.
2) Concurrent validation.
3) Retrospective validation.
1) Prospective validation: - In prospective validation the validation protocol is executed before the process is put into the commercial use. During the product development stage the production process should be broken down into individual steps. Each step should be evaluated on the basis of Experience or theoretical considerations to determine the critical parameters that may affect the quality of finished product.
2) Concurrent validation: - It is similar to prospective, except the operating firm will sell the product during the qualification runs, to the public as its market price. This validation involves in process monitoring of critical processing steps and product testing which helps to generate documented evidence to show that production process is in a state of control.
3) Retrospective validation: - In this historic data is taken from the records of the completed production batches are used to provide the documented evidence that the process has been in state of control prior to the request for such evidence.
4) Revalidation: - It is the repetition of validation process or part of it. This is carried out when there is any change or replacement in formulation, equipment plan or site location, batch size and in the case of sequential batches that do not meet product specifications and is also carried out at specific time intervals in case of no changes.
Stages of process validation: - There are 3 Stages of process validation they are
Stage 1:- Process design or pre-qualification: The commercial process is defined during this stage based on the knowledge gained through development and scale up activities.
Stage 2:- Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing.
Stage 3:- Continued process verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
Tablets are comprises of mixture of active ingredients and excipients which are compressed or molded into a cylindrical or biconvex solid. The principle objective of this dosage form is to achieve a predictable therapeutic response to a drug which is included into a formulation which is capable of large scale manufacturing with reproducible product quality. Their cost is lowest of all the oral dosage forms. They are lightest and compact of all oral dosage form.
Identify the key physicochemical properties of the drug substance that need to be considered in developing the formulations of tablet, such as the following:
1. Solubility of the drug substance throughout the physiological pH range: - Depending on the solubility of the drug, a surfactant may be needed to enhance dissolution.
2. Particle size distribution and surface area: The particle size distribution of the drug may determine what grade of an excipient (e.g., microcrystalline cellulose) to use.
3. Morphology: If the drug is amorphous or has different polymorphs, certain excipients may be used to prevent conversion of the drug to other physical forms.
4. True and bulk density: An excipient (e.g., diluents) that has a similar bulk density as the drug may be selected to minimize segregation, especially with a direct compression formulation.
5. Material flow and compressibility: A free flowing, highly compressible material such as microcrystalline cellulose may be used for drugs with poor flow or compressibility properties.
6. Hygroscopicity: Special environmental working conditions may be required ensure that moisture is not picked up during material storage or handling and during the manufacture of the tablet dosage form.
6. Melting point: If the drug has a low melting point, a direct compression formulation may need to be developed instead of a wet granulation formulation to avoid drying the material and potentially melting or degrading the drug.
Strategy for the industrial process validation of tablet dosage form: -
1. The use of different lots of Raw material should be included.
2. Batches should be run in succession in different shifts and days.
3. Batches should be manufactured in equipments and facilities that are designed for the commercial manufacturing.
4. Critical process parameters should set within their operating Ranges and should not undergo upper and lower limits of these ranges during the operation.
5. Failure to meet the requirement of protocol with respect to the process input and output must be subjected to process qualification and subsequent revalidation.
Process validation protocol: - It is a written plan which states that how will be the validation conducted including test parameters, product characteristics, production and packaging equipments and the acceptance criteria. This document gives the critical steps of the manufacturing process that should be measured and allowable range of variability and the manner in which the system is to be tested. The validation protocol provides a synopsis of hope what is to be accomplished. It should list the selected process and control parameters. State the number of batches which are to be included in to a study and specify how the data once assembled and be treated for relevance. The date of approval of protocol should be noted down by the validation team. In the case where the protocol is altered or modified appropriate reasons for such change must be documented.
Process Evaluation and Selection: - Determine the unit operations needed to manufacture the tablets and their critical process parameters.
1. Mixing or Blending
The mixing or blending unit operation may occur once or several times during the tablet manufacture. For example, a direct compression formulation may involve one blending step in which the drug and the excipients are blended together prior to compression. A wet granulation formulation may require two mixing/blending steps: (1) prior to granulating to have a uniform drug/excipient mixture, and (2) after milling the dried granulation to add other excipients, such as the lubricant. Some or all the items provided in this section may therefore be pertinent for validation, depending on the mixing or blending objective.
The following physical properties of the drug and excipients are factor in creating a uniform mix or blend:
Particle size distribution
Materials that have similar physical properties will be easier to form a uniform mix or blend and will not segregate as readily as materials with large differences.
Mixing or blending technique: Diffusion (tumble), convection (planetary or high intensity), or pneumatic (fluid bed) techniques can be used to mix or blend materials. Determine the technique that is required for the formulation or process objective. It may be different, depending on whether you are mixing the drug and excipients for a direct compression formulation or adding the lubricant (e.g., magnesium stearate) to the granulation.
Mixing or blending speed: Determine the intensity (low/high shear) and/or speed (rpm) of the mixing or blending. Mixing the drug and excipient will require more intense mixing than adding the lubricant to the final blend.
Mixing or blending time: How much mixing or blending is required to obtain a uniform mixture? The mixing or blending time will be dependent on the mixing or blending technique and speed. Experiments should be done to determine if the materials can be over mixed, resulting in demixing or segregation of the materials. Demixing can occur due to the physical property differences (e.g., particle size distribution and density). For example, demixing can occur in a direct compression formulation in which the drug substance is micronized (5 microns) and the excipients are granular (500–1000 microns).
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